A growing body of research reveals that Amyotrophic Lateral Sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy metabolism and lower fat-free mass compared to healthy controls. The mutant superoxide dismutasel (mSODI) mouse model of familial ALS (FALS) also exhibits bioenergetic defects, such as hypermetabolism and mitochondrial dysfunction. The pathophysiologoical relelvence of these abnormalities, however, remains largely elusive. In light of these metabolic observations, one might anticipate that a key enzyme affected in disease is AMP- activated protein kinase (AMPK), a master sensor and regulator of energy balance in organisms. In our laboratory, we have found that AMPK activity is increased in in-vitro and in-vivo mSODI models. Furthermore, downregulating AMPK activity in-vitro is neuroprotective. Based on these preliminary results, we hypothesize that specific bioenergetic defects in mSODI-induced motor neuron disease activate AMPK, and that AMPK activation adversely affects neuronal survival. The overall goals of this proposal are: 1) To assess bioenergetic defects in mS0D1 models and its relation to AMPK activation, and 2) To determine whether increased AMPK activity leads to mS0D1-induced motor neuron death and metabolic dysfunction. To address these goals, mixed spinal cultures infected with mSODI or WT S0D1-expressing viruses, as well as mSODI and WT S0D1 mice will be employed. Cellular bioenergetics at multiple timpoints of disease will be assayed, and AMPK activity will be monitored using different techniques. Endogenous AMPK activity will also be downregulated pharmacologically and genetically. AMPK dysfunction has been linked to metabolic disorders, such as type II diabetes and obesity. Furthermore, AMPK has been implicated in aging pathways, as well as neurological conditions, such as Alzheimer's disease and ischemia. This project ultimately hopes to further our understanding of the interplay between metabolic dysfunction and neurodegenerative disease, specifically in ALS, in order to develop alternative therapies to prevent and treat disease.